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The amyloid precursor protein (APP) was discovered in the 1980s as the precursor protein of the amyloid A4 peptide. The amyloid A4 peptide, also known as A-beta (Aβ), is the main constituent of senile plaques implicated in Alzheimer’s disease (AD). In association with the amyloid deposits, increasing impairments in learning and memory as well as the degeneration of neurons especially in the hippocampus formation are hallmarks of the pathogenesis of AD. Within the last decades much effort has been expended into understanding the pathogenesis of AD. However, little is known about the physiological role of APP within the central nervous system (CNS). Allocating APP to the proteome of the highly dynamic presynaptic active zone (PAZ) identified APP as a novel player within this neuronal communication and signaling network. The analysis of the hippocampal PAZ proteome derived from APP-mutant mice demonstrates that APP is tightly embedded in the underlying protein network. Strikingly, APP deletion accounts for major dysregulation within the PAZ proteome network. Ca2+-homeostasis, neurotransmitter release and mitochondrial function are affected and resemble the outcome during the pathogenesis of AD. The observed changes in protein abundance that occur in the absence of APP as well as in AD suggest that APP is a structural and functional regulator within the hippocampal PAZ proteome. Within this review article, we intend to introduce APP as an important player within the hippocampal PAZ proteome and to outline the impact of APP deletion on individual PAZ proteome subcommunities.
FIFO is the most prominent queueing strategy due to its simplicity and the fact that it only works with local information. Its analysis within the adversarial queueing theory however has shown, that there are networks that are not stable under the FIFO protocol, even at arbitrarily low rate. On the other hand there are networks that are universally stable, i.e., they are stable under every greedy protocol at any rate r < 1. The question as to which networks are stable under the FIFO protocol arises naturally. We offer the first polynomial time algorithm for deciding FIFO stability and simple-path FIFO stability of a directed network, answering an open question posed in [1, 4]. It turns out, that there are networks, that are FIFO stable but not universally stable, hence FIFO is not a worst case protocol in this sense. Our characterization of FIFO stability is constructive and disproves an open characterization in [4].
We study queueing strategies in the adversarial queueing model. Rather than discussing individual prominent queueing strategies we tackle the issue on a general level and analyze classes of queueing strategies. We introduce the class of queueing strategies that base their preferences on knowledge of the entire graph, the path of the packet and its progress. This restriction only rules out time keeping information like a packet’s age or its current waiting time.
We show that all strategies without time stamping have exponential queue sizes, suggesting that time keeping is necessary to obtain subexponential performance bounds. We further introduce a new method to prove stability for strategies without time stamping and show how it can be used to completely characterize a large class of strategies as to their 1-stability and universal stability.
Wehrheim, Maren H. ; Faskowitz, Joshua ; Sporns, Olaf ; Fiebach, Christian ; Kaschube, Matthias ; Hilger, Kirsten
Human functional brain connectivity can be temporally decomposed into states of high and low cofluctuation, defined as coactivation of brain regions over time. Rare states of particularly high cofluctuation have been shown to reflect fundamentals of intrinsic functional network architecture and to be highly subject-specific. However, it is unclear whether such network-defining states also contribute to individual variations in cognitive abilities – which strongly rely on the interactions among distributed brain regions. By introducing CMEP, a new eigenvector-based prediction framework, we show that as few as 16 temporally separated time frames (< 1.5% of 10min resting-state fMRI) can significantly predict individual differences in intelligence (N = 263, p < .001). Against previous expectations, individual’s network-defining time frames of particularly high cofluctuation do not predict intelligence. Multiple functional brain networks contribute to the prediction, and all results replicate in an independent sample (N = 831). Our results suggest that although fundamentals of person-specific functional connectomes can be derived from few time frames of highest connectivity, temporally distributed information is necessary to extract information about cognitive abilities. This information is not restricted to specific connectivity states, like network-defining high-cofluctuation states, but rather reflected across the entire length of the brain connectivity time series.
Vogel, Fabian W. ; Alipek, Sercan ; Eppler, Jens-Bastian ; Triesch, Jochen ; Bissen, Diane ; Acker-Palmer, Amparo ; Rumpel, Simon ; Kaschube, Matthias
Dendritic spines are considered a morphological proxy for excitatory synapses, rendering them a target of many different lines of research. Over recent years, it has become possible to image simultaneously large numbers of dendritic spines in 3D volumes of neural tissue. In contrast, currently no automated method for spine detection exists that comes close to the detection performance reached by human experts. However, exploiting such datasets requires new tools for the fully automated detection and analysis of large numbers of spines. Here, we developed an efficient analysis pipeline to detect large numbers of dendritic spines in volumetric fluorescence imaging data. The core of our pipeline is a deep convolutional neural network, which was pretrained on a general-purpose image library, and then optimized on the spine detection task. This transfer learning approach is data efficient while achieving a high detection precision. To train and validate the model we generated a labelled dataset using five human expert annotators to account for the variability in human spine detection. The pipeline enables fully automated dendritic spine detection and reaches a near human-level detection performance. Our method for spine detection is fast, accurate and robust, and thus well suited for large-scale datasets with thousands of spines. The code is easily applicable to new datasets, achieving high detection performance, even without any retraining or adjustment of model parameters.
Computing the diameter of a graph is a fundamental part of network analysis. Even if the data fits into main memory the best known algorithm needs O(n2) [3] with high probability to compute the exact diameter. In practice this is usually too costly. Therefore, heuristics have been developed to approximate the diameter much faster. The heuristic “double sweep lower bound” (dslb) has reasonably good results and needs only two Breadth-First Searches (BFS). Hence, dslb has a complexity of O(n+m). If the data does not fit into main memory, an external-memory algorithm is needed. In this thesis the I/O model by Vitter and Shriver [4] is used. It is widely accepted and has produced suitable results in the past. The best known external-memory BFS implementation has an I/O-complexity of W(pn B + sort(n)) for sparse graphs [5]. But this is still very expensive compared to the I/O complexity of sorting with O(N/B * logM/B (N/B)). While there is no improvement for the external-memory computation of BFS yet, Meyer published a different approach called “Parallel clustering growing approach” (PAR_APPROX) that is a trade-off between the I/O complexity and the approximation guarantee [6].
In this thesis different existing approaches will be evaluated. Also, PAR_APPROX will be implemented and analyzed if it is viable in practice. One main result will be that it is difficult to choose the parameter in a way that PAR_APPROX is reasonably fast for every graph class without using the semi external-memory Single Source Shortest Path (SSSP) implementation by [1]. However, the gain is small compared to external-memory BFS using this approach. Therefore, the approach PAR_APPROX_R will be developed. Furthermore, a lower bound for the expected error of PAR_APPROX_R will be proved on a carefully chosen difficult input class. With PAR_APPROX_R the desired gain will be reached.
Analysis of machine learning prediction quality for automated subgroups within the MIMIC III dataset
(2023)
The motivation for this master’s thesis is to explore the potential of predictive data analytics in the field of medicine. For this, the MIMIC-III dataset offers an extensive foundation for the construction of prediction models, including Random Forest, XGBOOST, and deep learning networks. These models were implemented to forecast the mortality of 2,655 stroke patients.
The first part of the thesis involved conducting a comprehensive data analysis of the filtered MIMIC-III dataset.
Subsequently, the effectiveness and fairness of the predictive models were evaluated. Although the performance levels of the developed models did not match those reported in related research, their potential became evident. The results obtained demonstrated promising capabilities and highlighted the effectiveness of the applied methodologies. Moreover, the feature relevance within the XGBOOST model was examined to increase model explainability.
Finally, relevant subgroups were identified to perform a comparative analysis of the prediction performance across these subgroups. While this approach can be regarded as a valuable methodology, it was not possible to investigate underlying reasons for potential unfairness across clusters. Inside the test data, not enough instances remained per subgroup for further fairness or feature relevance analysis.
In conclusion, the implementation of an alternative use case with a higher patient count is recommended.
The code for this analysis is made available via a GitHub repository and includes a frontend to visualize the results.
Local protein synthesis has re-defined our ideas on the basic cellular mechanisms that underlie synaptic plasticity and memory formation. The population of messenger RNAs that are localised to dendrites, however, remains sparsely identified. Furthermore, neuronal morphological complexity and spatial compartmentalisation require efficient mechanisms for messenger RNA localisation and control over translational efficiency or transcript stability. 3’ untranslated regions, downstream from stop codons, are recognised for providing binding platforms for many regulatory units, thus encoding the processing of the above processes. The hippocampus, a part of the brain involved in the formation, organisation and storage of memories, provides a natural platform to investigate patterns of RNA localisation. The hippocampus comprises tissue layers, which naturally separate the principle neuronal cell bodies from their processes (axons and dendrites). Identifying the full-complement of localised transcripts and associated 3’UTR isoforms is of great importance to understand both basic neuronal functions and principles of synaptic plasticity. These findings can be used to study the properties of neuronal networks as well as to understand how these networks malfunction in neuronal diseases.
Here, deep sequencing is used to identify the mRNAs resident in the synaptic neuropil in the hippocampus. Analysis of a neuropil data set yields a list of 8,379 transcripts of which 2,550 are localised in dendrites and/or axons. Using a fluorescent barcode strategy to label individual mRNAs shows that the relative abundance of different mRNAs in the neuropil varies over 5 orders of magnitude. High-resolution in situ hybridisation validated the presence of mRNAs in both cultured neurons and hippocampal slices. Among the many mRNAs identified, a large fraction of known synaptic proteins including signaling molecules, scaffolds and receptors is discovered. These results reveal a previously unappreciated enormous potential for the local protein synthesis machinery to supply, maintain and modify the dendritic and synaptic proteome.
Using advances in library preparation for next generation sequencing experiments, the diversity of 3’UTR isoforms present in localised transcripts from the rat hippocampus is examined. The obtained results indicate that there is an increase in 3’UTR heterogeneity and 3’UTR length in neuronal tissue. The evolutionary importance of the 3’UTR diversity and correlation with changes in species,tissue and cell complexity is investigated. The conducted analysis reveals the population of 3’UTR isoforms required for transcript localisation in overall neuronal transcriptome as well as the regulatory elements and binding sites specific for neuronal compartments. The configuration of poly(A) signals is correlated with gene function and can be further exploit to determine similar mechanisms for alternative polyadenylation.
Usage of custom specified methods for next-generation sequencing as well as novel approaches for RNA quantification and visualisation necessitate the development and implementation of new downstream analytic methods. Library methods for data-mining transcripts annotation, expression and ontology relations is provided. Usage of a specialised search engine targeting key features of previous experiments is proposed. A processing pipeline for NanoString technology, defining experimental quality and exploiting methods for data normalisation is developed. High-resolution in situ images are analysed by custom application, showing a correlation between RNA quantity and spatial distribution. The vast variety of bioinformatic methods included in this work indicates the importance of downstream analysis to reach biological conclusions. Maintaining the integrability and modularity of our implementations is of great priority, as the dynamic nature of many experimental techniques requires constant improvement in computational analysis.
Turi, Georg ; Gotthardt, Sascha ; Singer, Wolf ; Anh Vuong, The ; Munk, Matthias Hans Joachim ; Wibral, Michael
Event-related potentials (ERPs) are widely used in basic neuroscience and in clinical diagnostic procedures. In contrast, neurophysiological insights from ERPs have been limited, as several different mechanisms lead to ERPs. Apart from stereotypically repeated responses (additive evoked responses), these mechanisms are asymmetric amplitude modulations and phase-resetting of ongoing oscillatory activity. Therefore, a method is needed that differentiates between these mechanisms and moreover quantifies the stability of a response. We propose a constrained subspace independent component analysis that exploits the multivariate information present in the all-to-all relationship of recordings over trials. Our method identifies additive evoked activity and quantifies its stability over trials. We evaluate identification performance for biologically plausible simulation data and two neurophysiological test cases: Local field potential (LFP) recordings from a visuo-motor-integration task in the awake behaving macaque and magnetoencephalography (MEG) recordings of steady-state visual evoked fields (SSVEFs). In the LFPs we find additive evoked response contributions in visual areas V2/4 but not in primary motor cortex A4, although visually triggered ERPs were also observed in area A4. MEG-SSVEFs were mainly created by additive evoked response contributions. Our results demonstrate that the identification of additive evoked response contributions is possible both in invasive and in non-invasive electrophysiological recordings.
Trösemeier, Jan-Hendrik ; Rudorf, Sophia ; Lößner, Holger ; Hofner, Benjamin ; Reuter, Andreas ; Schulenborg, Thomas ; Koch, Ina ; Bekeredjian-Ding, Isabelle ; Lipowsky, Reinhard ; Kamp, Christel
Heterologously expressed genes require adaptation to the host organism to ensure adequate levels of protein synthesis, which is typically approached by replacing codons by the target organism’s preferred codons. In view of frequently encountered suboptimal outcomes we introduce the codon-specific elongation model (COSEM) as an alternative concept. COSEM simulates ribosome dynamics during mRNA translation and informs about protein synthesis rates per mRNA in an organism- and context-dependent way. Protein synthesis rates from COSEM are integrated with further relevant covariates such as translation accuracy into a protein expression score that we use for codon optimization. The scoring algorithm further enables fine-tuning of protein expression including deoptimization and is implemented in the software OCTOPOS. The protein expression score produces competitive predictions on proteomic data from prokaryotic, eukaryotic, and human expression systems. In addition, we optimized and tested heterologous expression of manA and ova genes in Salmonella enterica serovar Typhimurium. Superiority over standard methodology was demonstrated by a threefold increase in protein yield compared to wildtype and commercially optimized sequences.